Cyanomethyl(3-trifluoromethylphenoxy)(4-chlorophenyl)acetate

ABSTRACT

A method for the preparation of 2-acetamidoethyl(3trifluoromethylphenoxy)(4-chlorophenyl)acetate which comprises treating 2-aminoethyl (3-trifluoromethylphenoxy)-(4chlorophenyl)acetate with an acetylating agent. The 2acetamidoethyl(3-trifluoromethylphenoxy)(4-chlorophenyl)-acetate thus obtained is a hypocholesterolemic and hypolipemic agent which effectively reduces the concentration of cholesterol, triglycerides and other lipids in blood serum.

United States Patent [1 1 [111 3,860,628

Shuman Jan. 14, 1975 CYANOMETHYL(3- TRIFLUOROMETHYLPHENOXY)(4- Primary Examiner-Lewis Gotts CHLQROPHENYL)ACETATE Assistant Examiner-Dolph H. Torrence [75] Inventor: Richard F. Shuman, Westfield, NJ. figxz g jg 0r Flrm-Edmunde Rlcdl; [73] Assignee: Merck & Co., Inc., Rahway, NJ. 22 Filed: July 13, 1972 [57] ABSTRACT A method for the preparation of 2-acetumidoethyl(3- [21] Appl' 271447 trifluoromethylphenoxy)(4chlorophenyl)ucetzite which comprises treating Z-aminoethyl (3- 521 US. Cl..... 260/465 D, 260/465 B, 260/473 16, trifluoromethylphenoxyH4-chlomphenylmewc 2 0 544 M, 2 0 999 with an acetylating agent. The 2-acetamidocthyl(3- 51 Int. Cl. .i C07C 121/74 y p y)( ph nyl)-z1 tatc thus [58] Field of Search 260/465 D Obtained is a yp h ic an ypolipcmic agent which effectively reduces the concentration of [56] References Cit d cholesterol, triglycerides and other lipids in blood UNlTED STATES PATENTS semm- $517,051 6/1970 Bolhofer 260/465 X 1 Claim, N0 Drawings CYANOMETHYL(3- TRIFLUOROMETHYLPHENOXY)(4- CHLOROPHENYUACETATE This invention relates to a novel method for the preparation of 2-acetamidoethyl trifluoromethylphenoxy)-(4-chlorophenyl)acetate.

There is no clear agreement about the actual role of cholesterol and triglycerides in the localization of atherosclerotic plaques but numerous studies support the concept that cholesterol and triglycerides play a major role in the pathogenesis of atherosclerosis because along with other lipids and fibrin they accumulate in the arterial intima and subintima and produce arterial corrosion.

It is the purpose of this invention to describe a novel method for the preparation of Z-acetamidoethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate which product has proved effective in reducing the concentration of cholesterol, triglycerides and other lipids in blood serum. This compound induces a significant reduction in cholesterol and triglyceride levels in serum and it achieves this result with little or no irritation to the gastrointestinal tract.

According to this invention the preparation of 2- acetamidoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)-acetate is obtained by treating 2- aminoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate or its acid addition salt with an acetylating agent, for example, acetic anhydride, acetyl chloride, ketene, N-acetylimidazole and the like. The reaction may be conducted at a temperature in the range of from about -20C. to about 100C. The choice of a solvent is not critical to the reaction and,

OCHCOCH CI-I NH-Acyl in general, the process may be conducted in any suitably inert solvent in which the reactants are soluble such as acetic acid, benzene and the like. However, acetic acid is the preferred solvent. When the acid addition salt is employed, removal of the acid is effected CF CF O HCOCH CH NH 2 Y Z-Acetamidoethyl (3 -trifluoromethylphenoxy)-(4- chlorophenyl)acetate is a crystalline solidwhich can be [purified by recrystallization from a single solvent or III from a mixture of solvents, for example, by recrystallization from a lower alkanol such as methanol, ethanol, isopropanol and the like or from a mixture of these lower alkanols. Also, the product may be recrystallized from a mixture of toluene and hexane.

The 2-aminoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate (ll) or its acid addition salt may be prepared by either of two alternate processesv The first process comprises treating an N-acyl substituted Z-aminoethyl (3-trifluoromcthylphcnoxy) (4- chlorophenyl)acetate with a reducing agent, for example, a strong organic acid. The second method com prises the hydrogenation of cyanomethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate in the presence of a metal catalyst such as palladium and the like.

The first of the above-mentioned procedures for preparing the Z-aminoethyl (3trifluoromethylphenoxy) (4-chlorphenyl)acetate comprises treating an N-acyl substituted Z-aminoethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)-acetate with an acid, preferably, a

strong organic acid such as trifluoroacetic, hydrofluoric, hydrochloric, hydrobromic, sulfuric, p-toluencsulfonic and the like. This reaction may be conducted at a temperature in the range of from about 2()C. to about C. for a period of time of from about 0.5 hours to about 5 hours. While the particular solvent employed is not critical, it has been found convenient to employ as the solvent an excess ofthc particular acid which is used in the reaction. The following equation illustrates this process:

CF fi C OCHCOCH CH NR wherein the acyl radical is a mononuclear aralkoxycarbonyl radical, for example, an unsubstituted or substituted phenyl lower alkoxycarbonyl wherein the substituent is methoxy, chloro or nitro such as benzyloxyearbonyl, 4-methoxybenzyloxycarbo nyl, Z-methoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like.

The second method for preparing the 2-aminoethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetate comprises the catalytic hydrogenation of cyanomethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetate fi OCH OCH CH NHCCH 3,860,628 3 4 employing as the catalyst a metal catalyst such as palla- Due to the unstability of some of the Acyl-X comdium and the like with hydrogen under pressure. For pounds, especially those with methoxy substitucnts, it the purposes of isolation it has been found convenient is necessary to prepare them frsh before each reaction. to employ as the solvent an organic acid which will This reaction comprises treating a mononuclear aralkform an acid addition salt of the desired aminoethyl 5 anol, for example, an unsubstituted or substituted phecompound. Acids which may be employed include the nyl lower alkanol wherein the substituent is methoxy,

organic acids, for example, trifluoroacetic acid, acetic chloro or nitro, with phosgene in an inert solvent such acid or strong acids in aprotic solvents, particularly as diethyl ether at 0C. 1 ethers, for example, trifluoroacetic acid, methanesul- The following examples illustrate the process of this fonic acid, hydrogen chloride, trichloroacetic acid, invention. However, the examples are illustrative only benzenesulfonic acid, p-toluenesulfonic acid, and this invention should not be construed as being limp-nitrobenzenesulfonic acids in diethyl ether, tetrahyited thereto since other reaction conditions and-other drofuran, dioxane, dimethoxyethane, diglyme or trifunctionally equivalent reagents may be substituted glyme; a s aromatlc solvents Suchas benzene, t therefor to afford an identical Z-acetamidocthyl (3- ene, xylene and the like. The following equation lllUS- trifluoromethylphengxy) (4 h| h 1) mw trates this process: product. CF o I c1? OCHCOCH CN -9 OCHCOCH CH NH IV II The N-acyl Z-aminoethyl (3- EXAMPLE 1 trifluoromethylphenoxy)-(4-chlorophenyl)acetate is prepared by treating (3-trifluoromethylphenoxy) 3O 2-A ami 0e hyl(3- rifl 0r0m thylphcn xy) (4-chlorophenyl)acetyl chloride with N-acyl-2- 0r0phenyl)-11C flm aminoethanol. This reaction may be conducted at a Step A temperature in the range of from about C. to V about 100C; however, in general, the reaction is con- N-(Benzyloxycarbonyl)-2-flmmclhy| veniently conducted at ambient temperature. Any sol- (3-triflu0r0methylphen0xy) (4'chlomphcnyll-llcclillc vent which is inert or substantially inert to the reactants (3 T ifl th l h (4 chlomphcny|)ucctic y be p y such as benzene and the like It has acid (8.47 g., 0.0256 mole) is refluxed for two hours been found convenient to add to the reaction mixture with thionyl chloride (13.1 g., 0.1 1 mole). The excess a base such as pyridine and the like to react with any 4 thionyl chloride is removed under vacuum at 8090C.

hydrochloric acid formed during the reaction. The fol- The residue of (3-trifluoromethylphenoxy) (4-chlorolowing equation illustrates this process: phenyl)acetyl chloride is cooled to 25C. and dissolved CF CF O OCHLCI H0CH CH NHAcy1 9 @O HHOCH CH NH-ACYl v III wherein acyl is as defined above. in benzene (10 ml.). This solution is added over a five- Cyanomethyl (3-trifluoromethylphenoxy) (4- minute period to N(ben2yloxycarbonyl)-,2- chlorophenyl)acetate (1V) prepared by treating (3- aminoethanol (5g., 0.0256 mole), pyridine (2.43 g..

trifluoromethylphenoxy) (4- hl p yD tyl ch O- 0.0307 mole) and benzene (50 ml.). The reaction mixride (V) with formaldehyde cyanohydrin in a suitably ture is stirred for one hour at 2530C. Ether (25 ml.) inert solvent or mixture of inert solvents such as benis added and the mixture is extracted successively with zene-ether and the like. water (25 ml.), sodium bicarbonate (2 X 25 ml., l()%) The N-acyl-Z-aminoethanols (VI) employed in the and water (50 ml.). The ether-benzene solution is dried preparation of N-acyl-2-aminoethyl (3- vover sodium sulfate, filtered and the ether removed to trifluoromethylphenoxy) (4-chlorophenyl)acetate (lII) afford 12.5 g. (99.7% yield) of N-(benzyloxycarbonyU- are either known compounds or may be prepared by 2-aminoethyl (3-trifluoromethylphenoxy)-(4- treating 2-aminoethanol with a compound of the forchlorophenyl)acetate. mula: Acyl-X, wherein Acyl is as defined above and X Elemental analysis for C H ,ClF NO is halo such as chloro and the like in the presence of a Calc.: C, 59.12; H, 4.17; Cl, 6.98; F, 11.22; N, 2.76;

base such as sodium hydroxide and the like. Found: C, 59.18; H, 4.18; CI, 6.98; F, 10.95; N, 2.75.

2-Aminoethyl 3-trifluoromethylphenoxy)-( 4-chlorophenyl)acetate, trifluoroacetic Acid N-( benzyloxycarbonyl )-2-aminoethyl (3- trifluouromethylphenoxy) (4-chlorophenyl)acetate (6.04 g., 0.0119 mole) is dissolved in trifluoroacetic acid and heated at 60C. for 1.3 hours. The excess trifluoroacetic acid is removed under vacuum at 60C.

The residue is transferred to a separatory funnel and shaken with 3 X 25 ml. of hexane, decanting the supernatant layer each time. The resulting viscous product is dried under vacuum at 4050C. to afford 5.78 g. of crude product. A portion of this crude product (2.2 g.) is triturated with carbon tetrachloride (13 ml.) to afford 1.27 g. of substantially pure 2-aminoethyl (3- trifluoromethylphenoxy)-(4-chlorophenyl)acetate, trifluoroacetic acid, m.p. 105-111C.

Elemental analysis for C H CIF NO Calc.: C, 46.78; H, 3.31;Cl, 7.27; F, 23,37; N, 2.87;

Found: C, 45.58; H, 3.38; CI, 7.20; F, 23.37; N, 3.26.

By substituting for the N-(benzyloxycarbonyl)-2- aminoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate employed in Step B an equimolar quantity of N-( 4-methoxybenzylcarbonyl)-2- aminoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl )acetate, N-( 2- methoxybenzyloxycarbonyl)-2-aminoethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate, N- (2,4-dimethoxybenzyloxycarbonyl)-2-aminoethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate, N- (4-chlorobenzyloxycarbonyl)-2-aminoethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate and N-( 4-nitrobenzyloxycarbonyl)-2-aminoethyl 3- trifluoromethylphenoxy) (4-ch1orophenyl)acetate and by following substantially the procedure described therein, there is obtained 2-aminoethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate, trifluoroacetic acid.

Step C Z-Acetamidoethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetate 2-Aminoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate, trifluoroacetic acid (3 g., 0.00615 mole) is added to a solution of anhydrous sodium acetate (1.48 g., 0.018 mole) in acetic acid ml.) and acetic anhydride (15 ml.). The solution is stirred for four hours at 25C. The acetic anhydride and acetic acid are removed under vacuum at C. The residue is dissolved in ether and the ether solution is washed successively with water (30 ml.), potassium carbonate (30 ml., 10%) and with 10% sodium solution (30 ml.). The ether layer is dried over sodium sulfate, filtered and the ether removed to afford the crude product which is dissolved in toluene (4 ml.) to which is added hexane (6 ml.). The product is collected and dried to afford 1.35 g. of substantially pure 2- acetamidoethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate, m.p. 8588C.

Elemental analysis for C 9H 7ClF3N:

Calc.: C, 54.88; H, 4.12; Cl, 8.53; F, 13.71; N, 3.37;

Found: C, 54.63; 11,409; Cl, 8.58; F, 13.50; N, 3.25.

The 2-acetamidoethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetate may be further recrystallized from isopropanol to afford the product with a melting point of 93.5-95.5C.

By substituting for the acetic anhydride employed in Step C, an equimolar quantity of acetyl chloride, ketene or N-acetyl imidazole Z-aminoethyl (3- trifluoromethylphenoxy)(4-chlorophenyl)acetatc may be similarly acetylated to afford the 2-acetamidoethyl (3-trifluoromethylphenoxy)(4-chlorophenyl)-acctate.

EXAMPLE 2 2-Acetamidoethyl (3trifluoromethylphcnoxy) (4-chlorophcnyl)-acetate Step A Cyanomethyl (3-trifluoromethylphenoxy 4-chlorophenyl )acetatc To a solution of (3-trifluoromethylphenoxy) (4-chlorophenyl)acetyl chloride (0.0256 mole) in anhydrous benzene (30 ml.) is added sodium carbonate (0.05 mole) which had been dried under vacuum for 18 hours at C. To this mixture is added formaldehyde cyanohydrin (0.0256 mole) in ether (20 ml.) and the solution stirred for two hours at 25C. The reaction mixture is filtered to remove the inorganic salts and the benzene-ether solution of cyanomcthyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acetate is used in the next step without further purification.

Step B 2-Aminoethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetate, trifluoroacetic Acid To the benzene-ether solution of cyanomethyl (3- trifluoromethylphenoxy) (4-chlorophenyl)acctatc from Step A is added trifluoroacetic acid (2.92 g., 0.0256 mole) and 10% palladium-on-carbon (1.0 g.)v The reaction mixture is placed under 45 of hydrogen for three hours with shaking. The catalyst is re moved by filtration and the solvents removed under vacuum to afford crude product which is triturated with carbon tetrachloride (20 ml.) to afford substantially pure 2-aminoethyl (3-trifluoromethylphenoxy) ,(4-chlorophenyl)acetate, trifluoroacetic acid, m.p.

Z-Acetamidoethyl (3-trifluoromethylphenoxy)-(4-chlorophenyl)acetate By following substantially the procedure described in Example 1, Step C, 2-aminoethyl (3- trifluoromethylphenoxy)-(4-chlorophenyl)acetate, tri fluoroacetic acid may be converted to 2- acetamidoethyl (3trifluoromethylph'enoxy)(4- chlorophenyl)acetate.

PREPARATION OF STARTING MATERIALS A. N-Acyl-Z-aminoethanols N-(Benzyloxycarbonyl)-2aminoethanol 2-Aminoethano1 (6.1 g., 0.1 mole) is dissolved in 50 ml. of sodium hydroxide (2N, 0.1 mole) and the solution is cooled to 5C. To this solution is added benzylchloroformate (16.0 g., 0.0942 mole) dropwise over a -minute period. An additional 25 ml. of sodium hydroxide (2N, 0.05 mole) is added when half of the benzylchloroformate hasbeen added. The reaction mixture is stirred for hour at 0C; The white solids are collected and washed with cold water. The product is dissolved in ether (50 ml.) and the ether solution is washed successively with water (2 X 50 ml.), hydrochloric acid (2N, 2 X 50 ml.) and water (2 X 50 ml.). The ether solution is dried over sodium sulfate, filtered and the ether removed under vacuum to afford 1 1.0 g. (60%) of N-(benzyloxycarbonyl)-2-aminoethanol. The product is crystallized from diisopropyl ether (40 ml.) at C. The product is collected and washed with an ice cold mixture of petroleum ether in diethyl ether (4:1, 30 ml.) to afford 6.13 g. of N- (benzyloxycarbonyl)-2-aminoethanol, m.p. 4550C.

By following substantially the procedure described above and by substituting for the benzylchloroformate an equimolar quantity of 4-methoxybenzylchloroformate, 2-methoxybenzylchloroformatc, 2,4- dimethoxybenzylchloroformate, 4-chlorobcnzylchloroformate and 4-nitrobenzylchloroformatc there isproduced, respectively, N-(4-methoxybenzylcarbonyl)-2 aminoethanol, N-(2-methoxybenzyloxycarbonyl)-2- aminoethanol, N-(2,4-dimethoxybenzyloxycarbonyl)- 2-aminoethanol, N-(4-chlorobenzyloxycarbonyl)-2- aminoethanol and N-(4-nitrobenzyloxycarbonyl)-2- aminoethanol.

B. Acyl-X Compounds 4-Methoxybenzylchloroformate To a solution of phosgene (28.0 ml., 0.406 mole) in diethyl ether (200 ml.) at 0C. under a nitrogen atmosphere is added dropwise 4-methoxybcnzyl alcohol (27.6 g., 0.2 'mole) in diethyl ether ml.) over a 1 A2 hour period. The ether is removed under vacuum to afford 4-methoxybenzylchloroformate which is used immediately.

By substituting for the 4-methoxybenzyl alcohol an equimolar quantity of Z-mcthoxybenzyl alcohol, 2,4- dimethoxybenzyl alcohol, 4-chlorobcnzyl alcohol and 2 nitrobenzyl alcohol there is obtained, .rcspcctivcly,

2-methoxybenzylchloroformate, 2,4-dimcthoxybcnzylchloroformate, 4chlorobenzylchloroformatc and 4-nitrobenzylchloroformate.

Iclaim:

l. Cyanomethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate. 

